It is the goal of the Ovarian Cancer Institute to find an early diagnostic tool for this disease, to understand the molecular basis of ovarian cancer and to better understand the causes of chemotherapy resistance, leading to the ultimate goal of developing more effective therapies in the treatment of the disease.

Called the silent killer, ovarian cancer is the leading cause of death from gynecologic cancers in the United States. It will strike 1 in 57 women in America this year. Because there are no obvious symptoms, the cancer is often detected too late. OCI is dedicated to changing the odds for women who may face no better than an average 5-year survival rate.


THE RESEARCHERS

John McDonald, PhD, Chief Scientific Officer
A formal collaboration with the Georgia Institute of Technology and the Ovarian Cancer Institute has been established. Formerly Head of the Department of Genetics Department at the University of Georgia, Dr. John McDonald, now holds the position of Chair of the School of Biology at the Georgia Institute of Technology. Dr. McDonald, Chief Scientific Officer of the Institute, is a recognized world authority in molecular genetics and genomics. Also a member of Georgia Research Alliance's Advisory Committee, he is currently actively involved in the state wide initiative in vaccine development and the Georgia Tech-Emory Predictive Health Initiative. Dr. McDonald's combined skills in both molecular and computational genetics, uniquely qualify him to direct OCI's high-throughput genetic analysis approach to various stages and types of ovarian tumors.


THE TECHNOLOGY

Two state-of-the-art approaches are being taken toward the development of a diagnostic test. In one approach, proteins are isolated from serum samples taken from ovarian cancer patients, patients with other types of cancer (e.g., breast cancer and colon cancer) and normal healthy individuals. These proteins are being analyzed by 2-D gel electrophoresis and mass spectrometry to identify proteins that are differentially expressed in cancer patients and healthy individuals.

OCI scientists are currently involved in running similar tests of serum samples from ovarian cancer, breast cancer and colon cancer patients. These data are compared with samples from normal healthy women. Our goal is to develop a test that can reliably distinguish between different types of cancers common in women. In addition, our tests are designed such that the particular proteins that are aberrantly present in cancer patients can be identified. This is a very important piece of information relevant to the future development of new, non-surgical therapies in the treatment of ovarian cancer (see below).

The second approach being taken towards the development of an effective diagnostic test involves the application of microarray technology. In this approach, gene expression patterns in ovarian tumors are compared with those present in normal ovaries. Using this technology, the expression profiles of over 30,000 genes can be examined in a single experiment. Differences in the expression of genes encoding serum proteins are of special interest with regard to the development of a diagnostic blood test. Antibodies are produced against these serum proteins and an immunoassay is developed for the detection of these proteins in blood samples. Such immunologically based tests are often more sensitive and cost effective than those reliant on high technologies such as mass spectrometry. Immunologically based diagnostic tests can usually be carried out in a physician's office making the test less expensive and more widely accessible than tests that are reliant on specialized technologies.

In addition to developing a reliable diagnostic test, OCI scientists are striving to understand the causal basis of ovarian cancer. Such an understanding can lead to the development of innovative, non-surgical therapies in the treatment of the disease. For example, we are using microarray and proteomic technologies to determine if different types of ovarian cancers have specific proteins expressed on their cell surface. Such cell surface "signatures" will not only be useful in specifically classifying ovarian tumors, it may help identify specific targets for immunotherapies. In this approach, specific antibodies will be developed to attack proteins on the surface of ovarian cancer cells. Such therapies are desirable because they do not generate "collateral damage" of normal healthy cells as do current chemotherapies.

Another area of research interest to OCI scientists is the molecular basis of chemotherapy resistance. Some tumors respond very well to chemotherapy while others acquire resistance. By comparing the gene expression patterns in tumors that have become resistant to chemotherapy with patterns in samples of these same tumors prior to chemotherapy treatment, we hope to be able to identify those genes which impart resistance. Such knowledge may be used in the development of drugs to block the resistance pathway making all tumors responsive to treatment.

A third area of current research interest to OCI scientists is the role of chromatin structure changes in early tumor development. Chromatin is the name given to the complex of proteins associated with the DNA in our chromosomes. A number of laboratories have reported preliminary evidence that some of the very first steps in cancer development involve changes in chromatin structure. OCI scientists are involved in identifying the enzymes and target sites involved in modifying chromatin structure during early ovarian cancer development. Drugs can be designed to interfere with these enzymes thus arresting the cancer development process before it progresses to an advanced stage.

Good results depend upon the proper collection, preservation and identification of large numbers of tumor samples backed up by extensive patient histories.

Ovarian cancers are surgically removed and immediately snap frozen or otherwise preserved by a surgical team led by the OCI founder and CEO, Dr. Benedict Benigno. Dr. Benigno's group performs more ovarian cancer surgeries on a yearly basis than major cancer centers like Sloan Kettering in New York City. In addition to the 300+ samples provided by Dr. Benigno's group, we are in the process of establishing a network of collaborating gynecologists throughout the state of Georgia who are being trained to identify early staged (Stage I) ovarian tumors during routine hysterectomies and to quickly preserve these specimens upon surgical removal. An extensive medical history of all patients donating tissue to our project is being digitally maintained at the OCI offices in Atlanta. All tumor samples are characterized by collaborating pathologists at St. Joseph's and Northside Hospitals in Atlanta.

High-throughput molecular techniques insure rapid and precise analyses of tumor samples.

Tumor cells are isolated from bulk cancer tissue by Dr. Jeff Lee (Medical College of Georgia) using the latest Laser Capture Microdissection (LCM) technologies. Global patterns of RNA expression are monitored in cancer vs. control cells by microarray technology using the Affymetrix microchip system in the laboratory of OCI Chief Scientific Officer and Head of the Genetics Department at the University of Georgia, Dr. John F. McDonald. Proteins isolated from tissue and blood samples of OCI patients are analyzed by state-of-the-art 2-D gel electrophoresis and mass spectrometry in the laboratories of Dr. Arthur Grider (Department of Food and Nutrition) and Dr. Ronald Orlando (Complex Carbohydrate Center) at the University of Georgia.

State-of-the-art bioinformatics is needed for the proper analysis of high-throughput data.

Data storage and analysis is a major rate limiting step in the processing of the volumes of data being generated by the high-throughput genomic (microarray) and proteomic (2 D-gel, mass spectrometry) technologies employed in our program. OCI is fortunate to have an outstanding group of bioinformaticists on our team of collaborators. Dr. Eileen Kraemer (Department of Computer Science, UGA) and Dr. Susmita Data (Departments of Computer Science and Biology, GA State University) are involved in the analysis of our microarray data using a variety of gene expression analysis programs. Dr. May Wang (Department of Biomedical Engineering, GA Tech) has recently developed a new algorithm specifically designed to analyze high throughput microarray and mass spectrometry data. Dr. Wang has recently joined the OCI research team and is in the process of analyzing our data.

OCI researchers are engaged in cutting edge ovarian cancer research.

Innovative areas of research being pursued by OCI researchers include studies on the significance of genome-wide changes in patterns of chromatin structure that accompany very early stages in the tumorgenesis. In this regard, the McDonald lab has recently applied for a patent on behalf of OCI and the University of Georgia for a new method to monitor chromatin changes in tumor cells. Dr. Nathan Bowen has recently joined the OCI team after completing two years of post-doctoral research at the National Institutes of Health. Dr. Bowen is an expert in the area of chromatin modification. He will focus his research on changes in chromatin structure that are associated with early stages of ovarian cancer. Dr. Karen Cornell (Department of Small Animal Medicine, UGA) will lead a new research effort to implant human ovarian tumors into immunologically deficient mice. These mice will be treated with the same chemotherapies used to treat the human patients and tumors that develop resistance to the chemotherapies will be subject to microarray and proteomic analyses in an effort to understand the genetic basis of chemotherapy resistance. Dr. Erin Dickerson will soon be joining the OCI research team to lead a new research effort to inhibit the growth of blood vessels that "feed" developing ovarian tumors. Dr. Dickerson is coming to us from the Cancer Center at the University of Wisconsin (Madison) where she has been a major player in the development of new drugs designed to block angiogenesis (blood vessel growth) in developing tumors.

The OCI research team enjoys some unique advantages that could speed results.

A unique feature of the OCI research effort is that all of our scientific collaborators are working on the same tissue and blood samples from the same group of patients. This allows researchers to correlate and compare results from the same material using a variety of different techniques. Such an arrangement removes experimental "noise" due to biological variation among individuals and will reduce the time needed to arrive at significant results. In addition, our molecular results can be quickly correlated with our digitized medical history files using state-of-the-art computational methods. These unique features of the OCI research program provide a significant advantage in our efforts to develop new and innovative diagnostics and therapies for ovarian cancer.

OCI has several cutting edge advantages not the least of which is an exceptionally large tissue bank. (Dr. Benigno and his partners see more cases of ovarian cancer than any other private practice and many major cancer research centers in the country). Within a few years, OCI is expected to have the largest ovarian cancer gene expression (microarray) database in the world. This will provide us with the statistical power to identify even subtle genetic differences in ovarian cancer tissue that other laboratories will not be able to detect.

Ovarian Cancer Institute's research effort is in a very exciting growth phase. With adequate financial support, significant scientific breakthroughs will occur in the near future.